Overcoming resistance to BRAF V600E inhibition in melanoma by deciphering and targeting personalized protein network alterations

BRAF V600E melanoma patients often initially respond to targeted therapy but frequently relapse due to acquired drug resistance. Although these tumors are driven by the BRAF V600E mutation, they can diverge and become supported by varied signaling networks, necessitating individualized treatment strategies. Here, we compute high-resolution patient-specific altered signaling signatures (PaSS) using an information-theoretic approach that identifies several co-expressed subnetworks (‘unbalanced processes’) per tumor. We rationally design individualized drug combinations—often composed of FDA-approved agents—to concurrently target these processes. In vitro and in vivo validation demonstrates that PaSS-based combinations outperform standard anti-BRAF V600E or BRAF/MEK therapies, are highly selective across tumors, and can delay resistance. This approach is broadly applicable to designing patient-specific anti-melanoma combinations.

S. Vasudevan, E. Flashner-Abramson, Heba Alkhaiti, Sangita Roy Chowdhury, I. A. Adejumobi, D. Vlienski, S. Stefansky, A. M. Rubinstein, N. Kravchenko-Balasha